Sex-specific role for serotonin 5-HT 2A receptor in modulation of opioid-induced antinociception and reward in mice.

Autor: Sierra S; Department of Physiology and Biophysics, Virginia Commonwealth University School of Medicine, Richmond, VA, 23298, USA., Muchhala KH; Department of Pharmacology and Toxicology, Virginia Commonwealth University School of Medicine, Richmond, VA, 23298, USA., Jessup DK; Department of Pharmacology and Toxicology, Virginia Commonwealth University School of Medicine, Richmond, VA, 23298, USA., Contreras KM; Department of Pharmacology and Toxicology, Virginia Commonwealth University School of Medicine, Richmond, VA, 23298, USA., Shah UH; Department of Physiology and Biophysics, Virginia Commonwealth University School of Medicine, Richmond, VA, 23298, USA., Stevens DL; Department of Pharmacology and Toxicology, Virginia Commonwealth University School of Medicine, Richmond, VA, 23298, USA., Jimenez J; Department of Physiology and Biophysics, Virginia Commonwealth University School of Medicine, Richmond, VA, 23298, USA., Cuno Lavilla XK; Department of Physiology and Biophysics, Virginia Commonwealth University School of Medicine, Richmond, VA, 23298, USA., de la Fuente Revenga M; Department of Physiology and Biophysics, Virginia Commonwealth University School of Medicine, Richmond, VA, 23298, USA; Virginia Institute of Psychiatric and Behavioral Genetics, Virginia Commonwealth University, Richmond, VA, 23298, USA., Lippold KM; Department of Pharmacology and Toxicology, Virginia Commonwealth University School of Medicine, Richmond, VA, 23298, USA., Shen S; Department of Physiology and Biophysics, Virginia Commonwealth University School of Medicine, Richmond, VA, 23298, USA., Poklis JL; Department of Pharmacology and Toxicology, Virginia Commonwealth University School of Medicine, Richmond, VA, 23298, USA., Qiao LY; Department of Physiology and Biophysics, Virginia Commonwealth University School of Medicine, Richmond, VA, 23298, USA., Dewey WL; Department of Pharmacology and Toxicology, Virginia Commonwealth University School of Medicine, Richmond, VA, 23298, USA., Akbarali HI; Department of Pharmacology and Toxicology, Virginia Commonwealth University School of Medicine, Richmond, VA, 23298, USA., Damaj MI; Department of Pharmacology and Toxicology, Virginia Commonwealth University School of Medicine, Richmond, VA, 23298, USA., González-Maeso J; Department of Physiology and Biophysics, Virginia Commonwealth University School of Medicine, Richmond, VA, 23298, USA. Electronic address: javier.maeso@vcuhealth.org.
Jazyk: angličtina
Zdroj: Neuropharmacology [Neuropharmacology] 2022 May 15; Vol. 209, pp. 108988. Date of Electronic Publication: 2022 Feb 17.
DOI: 10.1016/j.neuropharm.2022.108988
Abstrakt: Opioids are among the most effective analgesics and the mainstay of pain management. However, concerns about safety and abuse liability have challenged their widespread use by the medical community. Opioid-sparing therapies include drugs that in combination with opioids have the ability to enhance analgesia while decreasing opioid requirement as well as their side effects. Sex differences in antinociceptive responses to opioids have received increasing attention in recent years. However, the molecular mechanisms underlying sex differences related to opioid-sparing adjuncts remain largely unexplored. Using warm water tail-withdrawal as a mouse model of acute thermal nociception, our data suggest that adjunctive administration of the serotonin 5-HT 2A receptor (5-HT 2A R) antagonist volinanserin dose-dependently enhanced potency of the opioid analgesic oxycodone in male, but not female, mice. This antinociceptive-like response induced by oxycodone was also augmented in 5-HT 2A R knockout (5-HT 2A R -/- ) male, but not female mice; an effect that was reversed by Cre-loxP-mediated selective expression of 5-HT 2A R in dorsal root ganglion (DRG) neurons of 5-HT 2A R -/- littermates. Pharmacological inhibition with volinanserin or genetic deletion in 5-HT 2A R -/- animals potentiated the ability of oxycodone to reduce DRG excitability in male mice. Adjunctive volinanserin did not affect oxycodone-induced conditioned place preference (CPP), whereas it reduced oxycodone-induced locomotor sensitization in male and female mice. Together, these results suggest that adjunctive volinanserin augments opioid-induced antinociception, but not abuse-related behavior, through a sex-specific signaling crosstalk mechanism that requires 5-HT 2A R expression in mouse DRG neurons. Ultimately, our results may pave the way for the clinical evaluation of volinanserin as a potential sex-specific opioid adjuvant.
(Copyright © 2022 Elsevier Ltd. All rights reserved.)
Databáze: MEDLINE
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